Regional Bacillus Calmette-Guérin Lymphadenitis After Initiating Antiretroviral Therapy in an Infant With Human Immunodeficiency Virus Type 1 Infection

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Many countries with a high prevalence of tuberculosis routinely immunize children with Bacillus Calmette-Guérin (BCG) at birth or as soon as possible thereafter, in accordance with the Expanded Programme on Immunisation guidelines.1 This policy has not been altered for countries with a high prevalence of human immunodeficiency virus type 1 (HIV-1) infection because the vaccine is effective in preventing tuberculosis (particularly disseminated forms of tuberculosis).2 In addition although the frequency of BCG-related complications may be slightly higher in HIV-1-infected infants compared with those born to HIV-negative mothers,3 these complications are usually mild, with disseminated BCG infection a rare event (reviewed by O'Brien et al.3). However, the infants studied in the literature did not receive potent antiretroviral therapy. Restoration of cellular immunity to mycobacterial antigens has been reported after potent antiretroviral therapy in adults4 and may be associated with clinical syndromes5 which occur as a result of immune restoration.6 Therefore HIV-infected infants who are immunized with BCG at birth and are subsequently treated with potent antiretroviral therapy may be at risk of clinical BCG infections as a result of restoration of cellular immunity to mycobacteria. We report the case of a male infant with vertically acquired HIV infection (Category C3) who developed suppurative regional BCG lymphadenitis 9 months after immunization, after combination antiretroviral therapy was commenced. Case report. The patient presented to our hospital at 8 months of age with respiratory failure after a 2-week history of nonproductive cough, increasing tachypnea and cyanosis. The past medical history included long term failure to thrive, surgical repair of an atrial septal defect and persistent oral candidiasis. He had been immunized at birth with BCG in Indonesia. On admission he had fever and a respiratory rate of 90 per min and was in respiratory failure (oxygen saturation, 80% in room air). A chest roentgenogram showed diffuse alveolar shadowing of both lung fields. Organisms compatible with Pneumocystis carinii were detected in a bronchoalveolar lavage specimen. His respiratory illness was managed with assisted ventilation, and he responded to high dosage intravenous trimethoprim-sulfamethoxazole and glucocorticoids. Serologic testing for HIV-1 antibodies was positive for the child and his parents. The child's initial plasma HIV-1 RNA concentration was 4.4 × 106 copies/ml and the blood CD4% was 10%. Zidovudine (120 mg/m2 four times a day) and lamivudine (4 mg/kg twice a day) were commenced 1 week after admission but were temporarily withheld for 2 weeks because of neutropenia. Two weeks after the recommencement of zidovudine and lamivudine, the patient returned with fever, poor feeding and suppurative right axillary and supraclavicular lymphadenopathy (Fig. 1). Intradermal injection of 0.1 ml of 100 IU/ml human purified protein derivative elicited 7 mm diameter of induration at 48 h, and mycobacterial lymphadenitis was diagnosed after a biopsy of the axillary lymph node. The patient's plasma HIV-1 RNA concentration at this stage was 7.7 × 104 copies/ml, and the blood CD4% had risen to 26%. Quadruple antimycobacterial therapy (isoniazid, rifampin, ethambutol and pyrazinamide) was commenced. Fever resolved and he began to thrive. Mycobacterium bovis (BCG strain) was isolated from material obtained from the lymph node biopsy.Fig. 1: Severe, suppurative regional BCG lymphadenitis after the commencement of combination antiretroviral treatment in a 9-month-old infant.Discussion. This child with Category C3 HIV infection developed suppurative regional BCG lymphadenitis which coincided with a marked increase in the proportion of CD4+ T cells in the peripheral blood and a >1.5-log reduction in his viral load after the commencement of combination antiretroviral therapy. Similar complications occur in 0 to 30% of HIV-1-infected infants not receiving antiretroviral therapy and in 2 to 18% of infants not infected with HIV-1.6 The onset of this child's lymphadenopathy coinciding with the improvement in his immune function and virologic indices after antiretroviral treatment suggests that the suppurative BCG lymphadenitis may have occurred as a result of restoration of his immune response to a previously latent infection with BCG. In recent years several reports have been published of clinical exacerbations of previously latent infections shortly after commencement of potent antiretroviral therapy (reviewed by Jacobson and French6). These illnesses are characterized by onset of fever (which is often prolonged) within 2 to 4 weeks of starting antiretroviral treatment, associated with localized tissue inflammation (in particular lymphadenitis, pneumonitis or hepatitis) and, in the case of mycobacterial infections, restored cutaneous delayed-type hypersensitivity responses to mycobacterial antigens. The pathogens most commonly involved are mycobacteria and cytomegalovirus, although other pathogens including hepatitis B-virus have also been implicated.6 A recent report of restoration of specific lymphocyte proliferation responses to tuberculin and cytomegalovirus in vitro, associated with a rise in the proportion of peripheral blood memory CD4+ T cells after potent antiretroviral treatment4 provides additional evidence that restoration of pathogen-specific immune responses may be responsible for these illnesses. The number of reported cases of immune restoration infections after potent antiretroviral therapy is small; therefore the frequency of these illnesses is undetermined. It is apparent, however, that they are confined to patients who have been profoundly immunodeficient for at least some period during the course of their HIV infection.6 How can we prevent restored immune responses to BCG from causing disease in immunized HIV-infected infants receiving potent antiretroviral therapy? First, patients who are infected with HIV-1 should not be immunized with BCG. The situation is more complex in countries with a high prevalence of tuberculosis in which the diagnosis of vertically acquired HIV-1 infection is delayed or not routinely available. The Expanded Programme on Immunisation guidelines recommend BCG immunization at or soon after birth for asymptomatic children born to HIV-infected mothers in situations where the risk of tuberculosis is high.1 The safety of these guidelines has been confirmed by a number of studies that have shown no significant increase in severe BCG-related complications in asymptomatic HIV-1-infected infants receiving BCG immunization in the first month of life.3 The risks associated with routine BCG immunization at birth are small and are likely to be outweighed by the reduction in disseminated tuberculosis that will occur because of universal BCG immunization in these countries. Therefore these guidelines should continue to be followed. It is unclear how best to manage the HIV-infected infant already immunized with BCG who is about to receive potent antiretroviral therapy. At present the authors recommend close observation of the patient during the first 2 months of potent antiretroviral treatment for signs of regional or disseminated BCG infection. Should such signs occur an early tissue diagnosis should be sought. Once a diagnosis of mycobacterial infection is made, the child should receive combination antimycobacterial treatment with at least three agents including isoniazid and rifampin, until the organism is confirmed as BCG, after which pyrazinamide should be ceased or substituted with ethambutol. Treatment should then be with three agents for the first 2 months and with rifampin and isoniazid alone for a further 6 months (total duration of treatment of 9 months).7 Protease inhibitors should be avoided during treatment of the BCG infection because rifampin induces their metabolism via the cytochrome P-450 pathway leading to subtherapeutic serum concentrations of these agents. Mary J. Sharp, M.B., B.S. Dominic F. J. Mallon, M.B., B.S., F.R.A.C.P.